Differential outcome of MEK1/2 inhibitor-platinum combinations in platinum-sensitive and -resistant ovarian carcinoma cells

Giacomo Cossa, Cinzia Lanzi, Giuliana Cassinelli, Nives Carenini, Noemi Arrighetti, Laura Gatti, Elisabetta Corna, Franco Zunino, Nadia Zaffaroni, Paola Perego

Research output: Contribution to journalArticle

Abstract

Deregulated pro-survival signalling plays a role in ovarian carcinoma drug resistance. Here, we show that cisplatin or oxaliplatin in combination with the MEK1/2 inhibitor CI-1040 resulted in a synergistic effect associated with enhanced apoptotic response in platinum-sensitive cells. The drug combinations were additive in platinum-resistant cells exhibiting increased phospho-ERK1/2, down-regulation of apoptosis-related factors (BAX, PUMA, FOXO1) and of phosphatases inhibiting ERK1/2 (DUSP5, DUSP6). Consistently, FOXO1 knockdown in sensitive cells reduced the efficacy of the combination treatment. Pharmacological targeting of ERK1/2 pathway increases cell sensitivity to platinum compounds by interfering with multiple events, ultimately favouring apoptosis induction in selected molecular backgrounds.

Original languageEnglish
Pages (from-to)212-224
Number of pages13
JournalCancer Letters
Volume347
Issue number2
DOIs
Publication statusPublished - Jun 1 2014

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Keywords

  • Drug resistance
  • FOXO1
  • MEK inhibitors
  • Ovarian carcinoma
  • Platinum compounds

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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